The present invention relates to contrast media comprising a complex of gadolinium (Gd) type contrast agent and a polymer. More particularly, the present invention relates to such contrast media wherein the polymer is capable of phase transition according to environmental changes, such as pH, light and temperature, to develop different water solubility, and to an imaging method comprising the use of said contrast media.
The progress in clinical image diagnosis in recent years is remarkable, and various image diagnoses, such as X ray CT (computed tomography), ultrasonic image diagnosis, MRI (magnetic resonance imaging) diagnosis, scintigraphy and the like, have been used to make a diagnosis of almost every part of the body. Along therewith, various contrast media suitable for such image diagnoses have been developed and found to be useful.
In particular, MRI diagnosis is a new diagnostic method which has been drawing much attention recently from the field of radiation diagnosis as well as entire medical fields. When compared to other contrast media, the contrast media for MRI are superior in concentration resolution in tissues and safety from the absence of exposure to X rays, so that they are considered to be clinically useful in locating lesions, grasping anatomical and functional images of normal and abnormal parts, and the like.
On the other hand, the detection capability thereof is not entirely satisfactory, because the detection targets are restricted to certain diseases and parts, and leaves room for the development of contrast media having higher functions.
Contrast media have been awaited that (1) permit detection at lower concentrations (small doses) (2) permit detection of specific target cells (e.g., tumor) with high sensitivity (3) cause no toxicity and (4) are quickly cleared from the body. In particular, the development of an MRI contrast medium has been desired, which has superior contrasting capability, which does not form images where imaging is not desired, such as at normal tissues, and which is capable of forming images only of tumor or specific organs.
It is therefore an object of the present invention to provide an MRI contrast medium having reinforced imaging capability and high function, which is specifically a highly functional MRI contrast medium, which does not form images where imaging is not desired, such as at normal cells, and which expresses imaging capability only at the target cells (e.g., tumor), thereby, in consequence, strikingly improving the detection sensitivity at tumor and the like. The present invention also aims at providing a highly functional MRI contrast medium for angiography, which shows high image forming capability only in blood to increase detection sensitivity.
The present inventors have conducted intensive studies in an attempt to achieve the above-mentioned objects and found that bonding of a polymer responsive to microenvironmental changes to a gadolinium (Gd) type MRI contrast agent successfully results in an MRI contrast medium capable of exhibiting its imaging capability, in other words, capable of on-off switching of imaging capability, only at the target parts. In addition, they have succeeded in achieving even more superior imaging capability by polymerization of said Gd type MRI contrast agent, which resulted in the completion of the invention.
Thus, the present invention provides the following.
(1) A contrast medium comprising a complex of a gadolinium (Gd) type contrast agent and a polymer, said polymer being capable of phase transition in response to environmental changes to develop different water solubility.
(2) The contrast medium of (1) above, wherein the Gd type contrast agent is a polymerized contrast agent.
(3) The contrast medium of (2) above, wherein the polymerized contrast agent has a liner alternating copolymer structure, and which is particularly a complex polymer of the Gd and poly(diethylenetriaminepentaacetic acid (DTPA)- 1,3-propanediamine (PDA)).
(4) The contrast medium of (1) or (2) above, wherein the environmental changes are changes in pH.
(5) The contrast medium of (4) above, wherein the polymer is a member selected from the group consisting of a polydiethylaminoethylmethacrylate (PDEAMA), a poly L-hystidine (PLH), a poly L-lysine (PLL), a poly(1-vinylimidazole) (PVI) and derivatives thereof.
(6) The contrast medium of (1) or (2) above, wherein the environmental changes are changes in light.
(7) The contrast medium of (6) above, wherein the polymer is poly[bis(4-dimethylamino)phenyl](4-vinylphenyl)-methyl-leukohydroxide or a derivative thereof.
(8) The contrast medium of (1) or (2) above, wherein the environmental changes are changes in temperature.
(9) The contrast medium of (8) above, wherein the polymer is poly(N-isopropylacrylamide) or a derivative thereof.
(10) The contrast medium of (1) or (2) above, wherein the environmental changes are changes in expression or distribution of enzyme in a living body.
(11) The contrast medium of (1) above, wherein the Gd type contrast agent is a polymer of a Gd complex and a polymer capable of phase transition in response to environmental changes to develop different water solubility, and the polymer is capable of phase transition in response to the same environmental changes to develop different water solubility.
(12) The contrast medium of (11) above, wherein the environmental changes are changes in pH.
(13) The contrast medium of (12) above, wherein the polymer to be comprised in the Gd type contrast agent and the polymer to be used to form a complex with said Gd type contrast agent are the same or different and each is a member selected from the group consisting of PDEAMA, PLH, PLL, PVI and derivatives thereof.
(14) The contrast medium of (13) above, which does not show imaging capability for a normal tissue but is capable of imaging a tumor tissue and/or an inflammatory tissue.
(15) The contrast medium of (11) above, wherein the Gd type contrast agent is a polymer comprising poly L-lysine and Gd-DTPA.
(16) The contrast medium of any of (1), (2) and (11) above, wherein the contrast medium has been graft copolymerized by further bonding with a synthetic polymer, particularly, a hydrophilic polymer or a polysaccharide.
(17) The contrast medium of (1) or (11) above, wherein the imaging capability can be reversibly controlled in response to environmental changes.
(18) A method for producing a contrast medium comprising a complex of a Gd type contrast agent and a polymer, said polymer being capable of phase transition in response to environmental changes to develop different water solubility.
(19) The method of (18) above, wherein the Gd type contrast agent is a polymerized contrast agent.
(20) The method of (18) or (19) above, wherein the environmental changes are changes in pH.
(21) The method of (20) above, wherein the polymer is a member selected from the group consisting of PDEAMA, PLH, PLL, PVI and derivatives thereof.
(22) The method of (18) above, wherein the Gd type contrast agent is a polymer of a Gd complex and a polymer capable of phase transition in response to environmental changes to develop different water solubility, and the polymer is capable of phase transition in response to the same environmental changes to develop different water solubility.
(23) The method of (22) above, wherein the environmental changes are changes in pH.
(24) The method of (23) above, wherein the polymer to be comprised in the Gd type contrast agent and the polymer to be used to form a complex with said Gd type contrast agent are the same or different and each is a member selected from the group consisting of PDEAMA, PLH, PLL, PVI and derivatives thereof.
(25) An imaging method comprising the use of a contrast medium comprising a complex of a Gd type contrast agent and a polymer, said polymer being capable of phase transition in response to environmental changes to develop different water solubility.
(26) The method of (25) above, wherein the Gd type contrast agent is a polymerized contrast agent.
(27) The method of (25) or (26) above, wherein the environmental changes are changes in pH.
(28) The method of (27) above, wherein the polymer is a member selected from the group consisting of PDEAMA, PLH, PLL, PVI and derivatives thereof.
(29) The method of (25) above, wherein the Gd type contrast agent is a polymer of a Gd complex and a polymer capable of phase transition in response to environmental changes to develop different water solubility, and the polymer is capable of phase transition in response to the same environmental changes to develop different water solubility.
(30) The method of (29) above, wherein the environmental changes are changes in pH.
(31) The method of (30) above, wherein the polymer to be comprised in the Gd type contrast agent and the polymer to be used to form a complex with said Gd type contrast agent are the same or different and each is a member selected from the group consisting of PDEAMA, PLH, PLL, PVI and derivatives thereof.
(32) The method of (31) above, which does not show imaging capability for a normal tissue but is capable of imaging a tumor tissue and/or an inflammatory tissue.
(33) The method of (25) or (29) above, wherein the imaging capability can be reversibly controlled in response to environmental changes.
(34) A commercial package comprising a contrast medium comprising a complex of a Gd type contrast agent and a polymer, said polymer being capable of phase transition in response to environmental changes to develop different water solubility, and a written matter associated therewith, the written matter stating that the contrast medium can or should be used for MRI.
(35) The commercial package of (34) above, wherein the Gd type contrast agent comprises a polymer of a Gd complex and a polymer capable of phase transition in response to environmental changes to develop different water solubility, and the polymer forming the complex with the Gd type contrast agent is capable of phase transition in response to the same environmental changes to develop different water solubility.